Reperfusion is the preferred clinical strategy for preservation of heart function after myocardial infarction (MI), but also results in amplified inflammatory responses and significant secondary damage including cardiomyocyte apoptosis. We have recently discovered that efferocytosis (i.e. anti-inflammatory phagocytic clearance of apoptotic cells) is a causal mediator of repair after non-reperfused MI. Specifically, mice deficient in the macrophage apoptotic cell receptor, MerTK, have prolonged inflammation and accelerated heart failure. The physiological changes that occur during reperfused MI (i.e. ischemia, reactive oxygen species (ROS) production) differ significantly from models of non-reperfused MI, that the casual significance of MerTK in clinically relevant reperfused MI remains to be determined. Furthermore, while MerTK is expressed on both recruited and cardiac resident macrophages, resident macrophages alone are sufficient to provide inflammation resolution and repair after MI. As reperfusion increases macrophage infiltration, this may result in less than effective efferocytosis, and subsequently prolong inflammation and impair cardiac remodeling. Reperfusion often fails to fully reoxygenate the heart, and nothing is known regarding how hypoxia affects efferocytosis-directed inflammation resolution. Our preliminary data suggest that hypoxia decreases macrophage MerTK expression and efferocytosis capacity. The transcription factor HIF- 1alpha is upregulated after myocardial infarction and is an important regulator of macrophage activation during hypoxia, though its importance for MerTK-mediated efferocytosis remains to be determined. Additionally, the secondary damage to the heart that occurs during reperfusion is mediated at least in part by production of ROS. Increased ROS production results in proteolytic inactivation of MerTK in other experimental systems, suggesting that reperfusion, despite its net benefit to the heart, may result in suboptimal efferocytosis and subsequent repair. As both hypoxia and reoxygenation may downregulate MerTK through distinct mechanisms, improvement of efferocytosis after reperfused MI may be a promising strategy to promote resolution of inflammation, limit myocardial damage, and enhance repair. The specific hypothesis of this proposal is that MerTK-mediated efferocytosis is required for resolution of inflammation and preservation of myocardial function after clinically relevant reperfused MI, but is naturally limited both by hypoxia and by reperfusion-induced ROS generation. This hypothesis will be tested using mouse models of reperfused myocardial infarction, and in vitro models of hypoxia and reoxygenation. The proposed studies will fill an important knowledge gap regarding the regulation and consequences of efferocytosis in clinically relevant reperfused MI. Furthermore, elucidation of mechanisms of oxidative regulation of efferocytosis has extensive translational potential, and will suggest novel therapies to promote resolution of inflammation in numerous hypoxic pathologies including MI.